This application is in response to the RFA "Development of Biomarkers of Aging" and is a proposal to continue and extend our current NIA-funded Biomarkers of Aging research project. Previous studies in this project have yielded a well-characterized panel of morphometric biomarkers of brain aging in three strains of rodents, and have provided systematic data on the temporal course of development of these markers. One of the most striking findings from the prior period was that caloric restrictions (CR), in contradistinction to its effects on non-neuronal measures of aging, had no effect on our biomarkers of brain aging. Thus, brain and peripheral processes of aging may be governed by different mechanisms. Consequently, it will also be important to find interventions that can after aspects of brain aging. It is proposed to build on the prior studies in these rodent strains to a) test several interventions which increasing evidence suggests may be able to modulate brain aging; and b) develop new, noninvasive markers that will rely on magnetic resonance imaging (MRI) and spectroscopy (MRS) methods. The previous work will allow us to validate these new non-lethal methods (MRS, MRI) in rodents and, in turn, to apply them to normally aging humans. In long term intervention studies, the degree of biological brain aging in treated and control animals will be quantified by unbiased stereological analyses of hippocampal anatomy, by assessment of performance in a radial arm maze, and by quantitative MRS for high energy phosphate species. The proposed long-term interventions in rodent strains will include modulation of glucocorticoid and calcium homeostatic functions, based on increasing evidence that these factors play roles in normal brain aging. Concurrently with these studies normal, non-demented human volunteers of various ages will be assessed by MRS and by MRI three dimensional volumetric analyses of the hippocampus, ventricles and other brain regions. Although several studies have suggested that normal brain aging can be quantified by MRI, this will be the first study to examine this possibility over the mature life span, with volumetric methods, and concurrent MRS measures of bioenergetics in the same individuals. Thus the next phase of this project is aimed at validating non-lethal biomarkers of progressive brain aging in humans and rodent models, and at defining potential therapeutic interventions that may be able to modulate the brain aging process, and thereby enhance quality of later life.